Antimalarial drug resistance is a serious international health problem and a major obstacle for malaria control efforts in Africa. A better understanding of the epidemiology and molecular mechanisms of antimalarial drug resistance is greatly needed. The overall goal of this project is to use clinical and laboratory studies to critically evaluate practical first-line therapies for uncomplicated malaria in a cohort of Ugandan children living in an area of high malaria endemicity. The specific aims of the project are: 1) to compare the efficacy of chloroquine, amodiaquine, and Fansidar as first-line agents for the treatment of uncomplicated falciparum malaria, 2) to use molecular epidemiologic tools to distinguish recrudescence from reinfection after antimalarial therapy, and 3) to correlate drug resistance with mutations in Plasmodium genes that may mediate resistance. Patients be randomized to three different first-line drug regimens and followed prospectively for 18 months to compare impact each regimen has on a number of primary and secondary clinical outcomes. For each documented case of malaria, and at serial time points, blood samples will be collected for isolation of parasite DNA. This material will allow us to genotype parasites over time, and thus determine if parasites that appear after therapy due to recrudescence of resistant parasites or reinfection. In addition, parasite DNA will be used to determine whether polymorphisms in key parasite genes mediate resistance. The results of these investigations will provide key information for the formulation of rational malaria treatment policies and contribute to our understanding of the mechanisms of antimalarial drug resistance.